STRUCTURAL BASIS OF CA2+-CALMODULIN-CALCINEURIN SIGNALLING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这些研究都不是专门针对艾滋病的，但这些研究都是为了了解T细胞激活背后的蛋白质-蛋白质相互作用。也有已发表的证据表明，钙-钙调素-钙调神经磷酸酶途径有助于在潜伏感染的细胞中重新激活卡波西肉瘤相关疱疹病毒。 这个子项目的总体目标是获得有关钙-钙调蛋白-钙调神经磷酸酶途径信号的详细结构和动力学信息。钙调神经磷酸酶(Calcineurin，CN)可被细胞微区内的钙信号局部激活，也可被广泛存在的细胞质内的钙信号激活，并通过使特定的磷酸丝氨酸或磷酸苏氨酸残基去磷酸化来控制其他细胞蛋白的活性。 CN在T细胞中具有显著的作用，它调节转录因子NFAT，从而调节细胞因子基因和其他与T细胞激活相关的基因的转录。CN的这种作用是临床免疫抑制药物环孢素A和他克莫司的靶点。CN还参与发育过程，包括心脏瓣膜和血管系统的正常形成，并参与病理生理变化，包括心肌肥大和损伤后血管再狭窄。 本项目致力于 (1)CN信号如何通过识别单个CN底物来定向； (2)CN信号如何通过与靶向蛋白和调节蛋白的相互作用而被定向； (3)启动和维持CN激活的构象变化； (4)将胞质钙信号转化为CN信号的构象变化和蛋白质-蛋白质相互作用的动力学。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. None of this research is specifically directed to AIDS, but the studies are directed toward understanding the protein-protein interactions underlying T cell activation. There is also published evidence that the Ca2+-calmodulin-calcineurin pathway contributes to reactivation of Kaposi sarcoma-associated herpesvirus in latently infected cells. The overall goal of this subproject is to obtain detailed structural and kinetic information on signalling in the Ca2+-calmodulin-calcineurin pathway. Calcineurin (CN) is activated either locally by Ca2+ signals in cellular microdomains or globally by widespread cytoplasmic Ca2+ signals, and controls the activity of other cellular proteins by dephosphorylating specific phosphoserine or phosphothreonine residues. CN has a prominent role in T cells, where it regulates the transcription factor NFAT and thereby the transcription of cytokine genes and other genes associated with T cell activation. This role of CN is the target of the clinical immunosuppressive drugs cyclosporin A and tacrolimus. CN is also implicated in developmental processes, including the proper formation of cardiac valves and the vascular system, and in pathophysiological changes, including myocardial hypertrophy and vascular restenosis after injury. This project addresses (1) how CN signalling is directed through recognition of individual CN substrates; (2) how CN signalling is directed through interaction with targeting and regulatory proteins; (3) the conformational changes that initiate and sustain CN activation; and (4) the kinetics of the conformational changes and protein-protein interactions that translate cytoplasmic Ca signals into CN signalling.